AXL kinase-mediated astrocytic phagocytosis modulates outcomes of traumatic brain injury.
AXL kinase-mediated astrocytic phagocytosis modulates outcomes of traumatic brain injury.
复制标题
AXL 激酶介导的星形细胞吞噬作用调节创伤性脑损伤的结果。
DOI：
10.1186/s12974-021-02201-3
复制
发表时间：
2021-07-07
影响因子：
9.3
通讯作者：
Chen G
中科院分区：
文献类型：
--
作者：
Zhou H;Hu L;Li J;Ruan W;Cao Y;Zhuang J;Xu H;Peng Y;Zhang Z;Xu C;Yu Q;Li Y;Dou Z;Hu J;Wu X;Yu X;Gu C;Cao S;Yan F;Chen G
创伤性脑损伤（TBI）后大脑微环境的复杂变化可能会导致神经损伤，而对此几乎没有有效的治疗干预措施。星形胶质细胞的反应性是神经炎症等微环境变化的关键之一，但其作用和支撑其的分子机制仍不清楚。雄性 C57BL/6J 小鼠接受受控皮质冲击 (CCI)，以建立 TBI 模型。脑室内注射AXL受体酪氨酸激酶(AXL)特异性配体、重组小鼠生长停滞特异性6(rmGas6)，并于造模后30分钟腹腔注射选择性AXL拮抗剂R428。 TBI 后评估包括神经行为评估、透射电子显微镜、免疫组织化学和蛋白质印迹。采用实时聚合酶链式反应 (RT-PCR)、siRNA 转染和流式细胞术对原代培养的星形胶质细胞进行机制评估。 AXL 主要在 TBI 后的星形胶质细胞中上调，并促进星形胶质细胞转变为具有吞噬退化神经元或碎片能力的表型。因此，这种星形细胞转化促进了神经炎症的限制和神经功能障碍的恢复。与 rmGas6 治疗的效果相反，星形胶质细胞中 AXL 的药理抑制显着降低了体内和原代星形胶质细胞培养物中星形胶质细胞的吞噬作用。 AXL 激活转录 1 (STAT1) 途径的信号转导器和激活剂，从而进一步上调 ATP 结合盒转运蛋白 1 (ABCA1)。此外，来自 GAS6 耗尽的 BV2 细胞的上清液在体外诱导星形胶质细胞吞噬作用的有限增强。我们的工作确定了 AXL 在星形胶质细胞通过 AXL/STAT1/ABCA1 途径转化为吞噬表型中的作用，该途径有助于将健康脑组织与损伤引起的细胞碎片分离，进一步改善 TBI 后的神经炎症和神经损伤。总的来说，我们的研究结果为 TBI 提供了潜在的治疗靶点。在线版本包含可在 10.1186/s12974-021-02201-3 获取的补充材料。
Complex changes in the brain microenvironment following traumatic brain injury (TBI) can cause neurological impairments for which there are few efficacious therapeutic interventions. The reactivity of astrocytes is one of the keys to microenvironmental changes, such as neuroinflammation, but its role and the molecular mechanisms that underpin it remain unclear. Male C57BL/6J mice were subjected to the controlled cortical impact (CCI) to develop a TBI model. The specific ligand of AXL receptor tyrosine kinase (AXL), recombinant mouse growth arrest-specific 6 (rmGas6) was intracerebroventricularly administered, and selective AXL antagonist R428 was intraperitoneally applied at 30 min post-modeling separately. Post-TBI assessments included neurobehavioral assessments, transmission electron microscopy, immunohistochemistry, and western blotting. Real-time polymerase chain reaction (RT-PCR), siRNA transfection, and flow cytometry were performed for mechanism assessments in primary cultured astrocytes. AXL is upregulated mainly in astrocytes after TBI and promotes astrocytes switching to a phenotype that exhibits the capability of ingesting degenerated neurons or debris. As a result, this astrocytic transformation promotes the limitation of neuroinflammation and recovery of neurological dysfunction. Pharmacological inhibition of AXL in astrocytes significantly decreased astrocytic phagocytosis both in vivo and in primary astrocyte cultures, in contrast to the effect of treatment with the rmGas6. AXL activates the signal transducer and activator of the transcription 1 (STAT1) pathway thereby further upregulating ATP-binding cassette transporter 1 (ABCA1). Moreover, the supernatant from GAS6-depleted BV2 cells induced limited enhancement of astrocytic phagocytosis in vitro. Our work establishes the role of AXL in the transformation of astrocytes to a phagocytic phenotype via the AXL/STAT1/ABCA1 pathway which contributes to the separation of healthy brain tissue from injury-induced cell debris, further ameliorating neuroinflammation and neurological impairments after TBI. Collectively, our findings provide a potential therapeutic target for TBI. The online version contains supplementary material available at 10.1186/s12974-021-02201-3.
登录
查看更多内容
影响因子：
7.3
作者：
Barth ND;Marwick JA;Vendrell M;Rossi AG;Dransfield I
通讯作者：
Dransfield I
影响因子：
4.6
作者：
Kim SY;Lim EJ;Yoon YS;Ahn YH;Park EM;Kim HS;Kang JL
通讯作者：
Kang JL
影响因子：
16.6
作者：
Arneson D;Zhang G;Ying Z;Zhuang Y;Byun HR;Ahn IS;Gomez-Pinilla F;Yang X
通讯作者：
Yang X
影响因子：
--
作者：
Jorge, RE;Robinson, RG;Arndt, S
通讯作者：
Arndt, S
影响因子：
7.6
作者：
Godbout, Jonathan P.;Moreau, Maite;Johnson, Rodney W.
通讯作者：
Johnson, Rodney W.